ABSTRACT Hereditary mutations in the BRCA1-associated protein 1 (BAP1) gene, causes a diverse cancer phenotype with at least four cancers, uveal (eye) melanoma (UM), mesothelioma (MMe), skin melanoma (CM), kidney cancer (RCC) and benign skin lesions (AST). Variants associated with blue eye color at the HERC2/OCA2 gene locus have been associated with increased risk for melanoma and non-melanoma skin cancers. Historically this has been thought to be due to the loss of dark pigmentation protection from ultraviolet (UV) light. However, other molecular mechanisms have been suggested including impact of the melanin precursors on DNA damage, angiogenesis and formation of reactive oxygen species. The goal of this study is to address the National Cancer Institute?s Provocative Question ?What molecular mechanisms influence disease penetrance in individuals who inherit a cancer susceptibility gene? by determining whether variants in HERC2/OCA2 impact the clinical phenotype associated with BAP1 germline mutations. We hypothesize that variants impacting the function and/or expression of OCA2 lead to modification of the penetrance of clinical phenotypes such as risk of UM and CM, through both pigmentary and non-pigmentary mechanisms. The molecular mechanisms of reduced functional OCA2 levels on different cancers associated with BAP1 gene will be tested in cell lines representative of four major cancers namely UM, CM, RCC and MMe by the following two aims: Aim 1: To determine if increased melanin precursors as the result of HERC2/OCA2 variants impact angiogenesis, DNA damage and reactive oxygen species and if this is enhanced in a BAP1 deficient background. Aim 2: To determine the impact of host loss of OCA2 on the in-vivo tumorigenesis of BAP1 mutant melanocytes. Impact: BAP1 germline mutations increase the risk of UM, CM, RCC and MMe. Mechanistic studies of the effect of HERC2/OCA2 variant on the different cancers associated with BAP1 gene will provide crucial information on how these factors interact to augment or suppress tumor development in patients. Understanding these interactions will ultimately provide important information on the role of melanin precursors on cancer risk via photo-protective and non-photo protective mechanisms. This may lead to new preventive and/or treatment strategies in these patients.